Cross-species research reveals that social isolation and loneliness operate through a destructive feedback cycle, where isolation impairs cognitive control and emotional regulation, which then increases social threat sensitivity and reduces social reward processing, further deepening isolation. The mechanism involves specific brain networks including prefrontal cortex, insula, and hippocampus, with molecular disruptions spanning neuroinflammation, cortisol dysregulation, myelin damage, and altered oxytocin and dopamine signaling. This finding fundamentally reframes how we understand social connection's role in brain health. Rather than viewing loneliness as merely correlating with cognitive decline, the evidence suggests it actively drives neurodegeneration through identifiable biological pathways. The self-perpetuating nature explains why isolated individuals often struggle to re-engage socially even when opportunities arise. For longevity-focused adults, this underscores social connection as a non-negotiable pillar of brain health, not just emotional wellbeing. The research also validates why purely cognitive interventions often fail without addressing the underlying social threat sensitivity. Most promising are multimodal approaches that simultaneously target the neural networks involved while providing structured social re-engagement, suggesting that effective loneliness interventions must be neurobiologically informed rather than purely behavioral.